Understanding the KRAS Mutation Landscape in Biliary Tract Cancer

The early wave of KRAS inhibitor approvals was built around G12C, the mutation researchers first learned how to target. But the mutation distribution in biliary tract cancer runs in a different direction, which shapes how many patients stand to benefit from the agents currently furthest along in development.

In an interview with CancerNetwork® following the 2026 Chicago Cholangiocarcinoma Symposium, Chih-Yi “Andy” Liao, MD, broke down the KRAS mutation landscape in biliary tract cancer and what it means for drug development. He outlined the relative prevalence of G12D, G12V, and G12C among patients with KRAS-mutant disease, noting that G12C, despite anchoring the first generation of KRAS inhibitors, accounts for only a small fraction. Liao cited the phase 2 data supporting adagrasib (Krazati) in this setting, including its inclusion in NCCN guidelines for patients with KRAS G12C–mutated cholangiocarcinoma based on the phase 1/2 KRYSTAL-1 study (NCT03785249), while noting that the mutation applies to only 1% of all biliary tract cancers.

Liao then walked through the classes of KRAS-targeted agents now in development: mutant-selective inhibitors that bind the ON or OFF state, pan-KRAS inhibitors that target any KRAS mutation, and tri-complex inhibitors that engage RAS in the ON state, either selectively or across KRAS, HRAS, and NRAS.

Liao is an associate professor of Medicine, associate director of Gastrointestinal Oncology, and co-director of the Neuroendocrine Tumor program at University of Chicago School of Medicine.

Transcript:

CancerNetwork: The KRAS landscape in biliary tract cancer skews toward G12D and G12V rather than the G12C that drove early KRAS inhibitor approvals. What are the implications for cholangiocarcinoma specifically? Are multiselective RAS(ON) inhibitors a realistic near-term option for these patients?

Liao: KRAS mutations come in different forms. For [patients with] biliary tract cancer who have a KRAS mutation, the most prevalent one is KRAS G12D. Of patients who have a KRAS mutation, 41% have the G12D mutation, and 23% have the G12V mutation. KRAS G12C is only 6% of KRAS-mutant biliary tract cancers, and 30% of patients have a different KRAS mutation. Now, KRAS G12C inhibitors were the first to come to market because that was the one we discovered how to target first. There has definitely been a lot of exciting phase 2 data. For example, adagrasib [Krazati], a KRAS G12C inhibitor, is now listed in the NCCN guidelines as a treatment to consider for patients with cholangiocarcinoma whose tumors have the KRAS G12C mutation. That’s based on the KRYSTAL-1 study, which showed a response rate of 41.7%, which is pretty impressive for second-line therapy in cholangiocarcinoma. However, if you look at all biliary tract cancers, only 1% of them have the KRAS G12C mutation. How do we target these other, more common mutations such as G12D? Now, we finally have some data in cholangiocarcinoma with small molecule inhibitors for KRAS G12D.

As for your question about the multi-selective RAS(ON) inhibitors, KRAS inhibitors come in many different forms. You can have mutant-selective KRAS inhibitors, for example G12C inhibitors, which can target the OFF state or the ON state. You can have pan-KRAS inhibitors, which can target any KRAS mutation. Then, you have these tri-complex inhibitors that target RAS in the ON state. They can either be selective for a single mutation, or they can be multi-RAS inhibitors, for example targeting KRAS, HRAS, and NRAS. One example of this type of drug is daraxonrasib [Rasonque], which has recently generated a lot of excitement, as it was approved for pancreatic cancer and totally revolutionized the treatment landscape for that disease.

Reference

Pant S, Yaeger R, Spira AI, KRYSTAL-1: activity and safety of adagrasib (MRTX849) in patients with advanced solid tumors harboring a KRASG12C mutation. J Clin Oncol. 2023;41(suppl 36):425082. doi:10.1200/JCO.2023.41.36_suppl.425082